Discovery of an efficacious KDM5B PROTAC degrader GT-653 up-regulating IFN response genes in prostate cancer.

Epigenetic alterations promote cancer development by regulating the expression of various oncogenes and anti-oncogenes. Histone methylation modification represents a pivotal area in epigenetic research and numerous publications have demonstrated that aberrant histone methylation is highly correlated with tumorigenesis and development. As a key histone demethylase, lysine-specific demethylase 5B (KDM5B) demethylates lysine 4 of histone 3 (H3K4) and serves as a transcriptional repressor of certain tumor suppressor genes. Meanwhile, KDM5B inhibits STING-induced intrinsic immune response of tumor cells or recruits SETDB1 through non-enzymatic function to silence reverse transcription elements to promote immune escape. The conventional small molecule inhibitors can only inhibit the enzymatic function of KDM5B with no effect on the non-enzymatic function. In the article, we present the development of the first series of KDM5B degraders based on CPI-455 to inhibit the non-enzymatic function. Among them, GT-653 showed optimal KDM5B degradation efficiency in a ubiquitin proteasome-dependent manner. GT-653 efficiently reduced KDM5B protein levels without affecting KDM5B transcription. Interestingly, GT-653 increased H3K4me3 levels and activated the type-I interferon signaling pathway in 22RV1 cells without significant phenotypic response on cell proliferation.

Design and Characterization of Deformable Superstructures Based on Amine-Acrylate Liquid Crystal Elastomers.

Deformable superstructures are man-made materials with large deformation properties that surpass those of natural materials. However, traditional deformable superstructures generally use conventional materials as substrates, limiting their applications in multi-mode reconfigurable robots and space-expandable morphing structures. In this work, amine-acrylate-based liquid crystal elastomers (LCEs) are used as deformable superstructures substrate to provide high driving stress and strain. By changing the molar ratio of amine to acrylate, the thermal and mechanical properties of the LCEs are modified. The LCE with a ratio of 0.9 exhibited improved polymerization degree, elongation at break, and toughness. Besides an anisotropic finite deformation model based on hyperelastic theory is developed for the LCEs to capture the configuration variation under temperature activation. Built upon these findings, an LCE-based paper-cutting structure with negative Poisson's ratio and a 2D lattice superstructure model are combined, processed, and molded by laser cutting. The developed superstructure is pre-programmed to the configuration required for service conditions, and the deformation processes are analyzed using both experimental and finite element methods. This study is expected to advance the application of deformable superstructures and LCEs in the fields of defense and military, aerospace, and bionic robotics.

Stabilization of low-cost phase change materials for thermal energy storage applications.

Sodium sulfate decahydrate (Na2SO4.10H2O, SSD), a low-cost phase change material (PCM), can store thermal energy. However, phase separation and unstable energy storage capacity (ESC) limit its use. To address these concerns, eight polymer additives-sodium polyacrylate (SPA), carboxymethyl cellulose (CMC), Fumed silica (SiO2), potassium polyacrylate (PPA), cellulose nanofiber (CNF), hydroxyethyl cellulose (HEC), dextran sulfate sodium (DSS), and poly(sodium 4-styrenesulfonate) (PSS)-were used to explore several stabilization mechanisms. The ESC of PCMs deteriorated when thickeners, SPA, PPA, and CNF, were added. DSS-modified PCMs exhibited greater stability up to 150 cycles. Rheology measurements indicated that DSS did not impact SSD viscosity significantly during stabilization. Dynamic light scattering showed that DSS reduces SSD particle size and electrostatically suspends salt particles in a stable homogeneous solution, avoiding phase separation. This study proposes a promising method to improve the thermal stability of salt hydrate PCMs by utilizing polyelectrolyte-salt hydrate mixture for thermal energy storage applications.

One-Step Manufacturing of Supramolecular Liquid-Crystal Elastomers by Stress-Induced Alignment and Hydrogen Bond Exchange.

Liquid-crystal elastomers (LCEs) capable of performing large and reversible deformation in response to an external stimulus are an important class of soft actuators. However, their manufacturing process typically involves a multistep approach that requires harsh conditions. For the very first time, LCEs with customized geometries that can be manufactured by a rapid one-step approach at room temperature are developed. The LCEs are hydrogen bond (H-bond) crosslinked main chain polymers comprising flexible short side chains. Applying a stretching/shear force to the LCE can simultaneously induce mesogen alignment and H-bond exchange, allowing for the formation of well-aligned LCE networks stabilized by H-bonds. Based on this working principle, soft actuators in fibers and 2D/3D objects can be manufactured by mechanical stretching or melt extrusion within a short time (e.g. <1 min). These actuators can perform reversible macroscopic motions with large, controlled deformations up to 38 %. The dynamic nature of H-bonds also provides the actuators with reprocessability and reprogrammability. Thus, this work opens the way for the one-step and custom manufacturing of soft actuators.

Current advances of small molecule E3 ligands for proteolysis-targeting chimeras design.

Proteolysis-targeting chimeras (PROTACs) as an emerging drug discovery modality has been extensively concerned in recent years. Over 20 years development, accumulated studies have demonstrated that PROTACs show unique advantages over traditional therapy in operable target scope, efficacy, and overcoming drug resistance. However, only limited E3 ligases, the essential elements of PROTACs, have been harnessed for PROTACs design. The optimization of novel ligands for well-established E3 ligases and the employment of additional E3 ligases remain urgent challenges for investigators. Here, we systematically summarize the current status of E3 ligases and corresponding ligands for PROTACs design with a focus on their discovery history, design principles, application benefits, and potential defects. Meanwhile, the prospects and future directions for this field are briefly discussed.

Discovery of Pyrimidinediamine Derivatives as Potent Methuosis Inducers for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a leading malignancy among women that currently lack effective targeted therapeutic agents, and the limitations of treatment have prompted the emergence of new strategies. Methuosis is a novel vacuole-presenting cell death modality that promotes tumor cell death. Hence, a series of pyrimidinediamine derivatives were designed and synthesized through evaluation of their abilities that inhibit proliferation as well as induce methuosis against TNBC cells. Among them, JH530 showed excellent anti-proliferative activities and vacuolization capacity in TNBC. The mechanism research indicated that JH530 caused cell death through inducing methuosis of cancer cells. Furthermore, JH530 inhibited tumor growth remarkably in the HCC1806 xenograft model without an apparent decrease in body weight. Overall, JH530 is a methuosis inducer that displayed remarkable suppression of TNBC growth in vitro and in vivo, which provides a basis for the future progress of more small molecules for TNBC treatment.

Small-molecule Modulators Targeting SHP2 for Cancer Therapy.

BACKGROUND: SHP2 is a protein tyrosine phosphatase that is extensively involved in several signaling pathways related to cancer occurrence, and thus SHP2 has been proposed as an attractive target for cancer treatment. METHODS: After a brief introduction of SHP2, we provided a short overview of the structure, function and regulation mechanism of SHP2 in cancer occurrence. Then, this perspective focused on the current therapeutic strategies targeting SHP2, including SHP2 PTP inhibitors, SHP2 allosteric inhibitors and SHP2-targeting PROTACs, and discussed the benefits and defects of these strategies. Finally, the opportunities and challenges were presented. RESULTS: SHP2 regulated RAS-ERK, PI3K-AKT, JAK-STAT and PD-1/PD-L1 signaling pathways involved in the pathogenesis of cancer via conformations conversion. Current therapeutic strategies targeting SHP2, especially SHP2 allosteric inhibitors, hold significant potency and have broad application prospects for cancer therapy. CONCLUSION: In summary, SHP2 is a promising therapeutic target, and strategies targeting SHP2 offer an alternative program for cancer patients.

Research Progress of Electrically Driven Multi-Stable Cholesteric Liquid Crystals.

Electrically driven multi-stable cholesteric liquid crystals can be used to adjust the transmittance of incident light. Compared with the traditional liquid crystal optical devices, the multi-stable devices only apply an electric field during switching and do not require a continuous electric field to maintain the various optical states of the device. Therefore, the multi-stable devices have low energy consumption and have become a research focus for researchers. However, the multi-stable devices still have shortcomings before practical application, such as contrast, switching time, and mechanical strength. In this article, the latest research progress on electrically driven multi-stable cholesteric liquid crystals is reviewed, including electrically driven multi-stable modes, performance optimization, and applications. Finally, the challenges and opportunities of electrically driven multi-stable cholesteric liquid crystals are discussed in anticipation of contributing to the development of multi-stable liquid crystal devices.

B-cell Lymphoma 6 Inhibitors: Current Advances and Prospects of Drug Development for Diffuse Large B-cell Lymphomas.

B-cell lymphoma 6 (BCL6) is a transcriptional repressor that regulates the differentiation of B lymphocytes and mediates the formation of germinal centers (GCs) by recruiting corepressors through the BTB domain of BCL6. Physiological processes regulated by BCL6 involve cell activation, differentiation, DNA damage, and apoptosis. BCL6 is highly expressed when the gene is mutated, leading to the malignant proliferation of cells and drives tumorigenesis. BCL6 overexpression is closely correlated with tumorigenesis in diffuse large B-cell lymphoma (DLBCL) and other lymphomas, and BCL6 inhibitors can effectively inhibit some lymphomas and overcome resistance. Therefore, targeting BCL6 might be a promising therapeutic strategy for treating lymphomas. Herein, we comprehensively review the latest development of BCL6 inhibitors in diffuse large B-cell lymphoma and discuss the overview of the pharmacophores of BCL6 inhibitors and their efficacies in vitro and in vivo. Additionally, the current advances in BCL6 degraders are provided.

H-Bonding Room Temperature Phosphorescence Materials via Facile Preparation for Water-Stimulated Photoluminescent Ink.

Pure organic room-temperature phosphorescence (RTP) materials built upon noncovalent interactions have attracted much attention because of their high efficiency, long lifetime, and stimulus-responsive behavior. However, there are limited reports of noncovalent RTP materials because of the lack of specific design principles and clear mechanisms. Here, we report on a noncovalent material prepared via facile grinding that can emit fluorescence and RTP emission differing from their components' photoluminescent behavior. Exciplex can be formed during the preparation process to act as the minimum emission unit. We found that H-bonds in the RTP system provide restriction to nonradiative transition but also enhance energy transformation and energy level degeneracy in the system. Moreover, water-stimulated photoluminescent ink is produced from the materials to achieve double-encryption application with good resolution.

Spatial Patterning of Fluorescent Liquid Crystal Ink Based on Inkjet Printing.

Fluorescent cholesteric liquid crystal materials (FCLC) with aggregation-induced emission (AIE) properties can effectively solve the contradiction between aggregation-induced quenching (ACQ) and liquid crystal self-assembly when light-emitting materials are aggregated, and they have great application value in the fields of anti-counterfeit detection and information hiding. However, generating a visually appealing design, logo, or image in the application typically requires an intricate fabrication process, such as the use of prefabricated molds and photomasks, which greatly limits the practical application of FCLC materials. Herein is reported a new method for spatially patterned liquid crystal (LC) microdroplet arrays using drop-on-demand inkjet printing technology. Through rational composition design, a spatial array composed of different liquid crystal microdroplets was established, and the array contains two entirely distinct but intact patterns at the same time, which can be reversibly switched under the irradiation of UV and natural light. This study provides a new method for the integrated preparation of different component liquid crystal materials.

Research Progress of Cholesteric Liquid Crystals with Broadband Reflection.

Cholesteric liquid crystal (ChLC) materials with broadband reflection are witnessing a significant surge in interest due to their unique ability to self-organize into a helical supra-molecular architecture and their excellent selective reflection of light based on the Bragg relationship. Nowadays, by the virtue of building self-organized nanostructures with pitch gradient or non-uniform pitch distribution, extensive work has already been performed to obtain ChLC films with a broad reflection band. This critical review systematically summarizes the optical background of the ChLCs with broadband reflection characteristics, methods to obtain broadband reflection of ChLCs, as well as the application in this area. Combined with the research status and the advantages in the field, the challenges and opportunities of applied scientific problems in the research direction are also introduced.

Programmable Shape Change in Semicrystalline Liquid Crystal Elastomers.

Liquid crystal elastomers (LCEs) are stimuli-responsive materials capable of reversible and programmable shape change in response to an environmental stimulus. Despite the highly responsive nature of these materials, the modest elastic modulus and blocking stress exhibited by these actuating materials can be limiting in some engineering applications. Here, we engineer a semicrystalline LCE, where the incorporation of semicrystallinity in a lightly cross-linked liquid crystalline network yields tough and highly responsive materials. Directed self-assembly can be employed to program director profiles through the thickness of the semicrystalline LCE. In short, we use the alignment of a liquid crystal monomer phase to pattern the anisotropy of a semicrystalline polymer network. Both the semicrystalline-liquid crystalline and liquid crystalline-isotropic phase transition temperatures provide controllable shape transformations. A planarly aligned sample's normalized dimension parallel to the nematic director decreases from 1 at room temperature to 0.42 at 250 °C. The introduction of the semicrystalline nature also enhances the mechanical properties exhibited by the semicrystalline LCE. Semicrystalline LCEs have a storage modulus of 390 MPa at room temperature, and monodomain samples are capable of generating a contractile stress of 2.7 MPa on heating from 25 to 50 °C, far below the nematic to isotropic transition temperature. The robust mechanical properties of this material combined with the high actuation strain can be leveraged for applications such as soft robotics and actuators capable of doing significant work.

Quantification of uric acid concentration in tears by using PDMS inverse opal structure surface-enhanced Raman scattering substrates: Application in hyperuricemia.

Hyperuricemia is closely related to a variety of diseases and has been listed as one of the twenty most persistent diseases in the 21st century by the United Nations. Therefore, strengthening the diagnosis of hyperuricemia has become imperative. Here, ordered inverse opal array structures (PAANs) composed of PDMS and gold nanoparticles (AuNPs) have been designed using a bottom-up self-assembly method. The structures exhibit a periodic distribution of hot spots, an enhancement factor (EF) of 4.22 × 104, and a relative standard deviation (RSD) of signal intensity of less than 5%, which can provide high reproducibility of SERS signals. The PAANs substrate is used to detect uric acid in the tears of patients with hyperuricemia, and the limit of detection is 6.03 µM. The significant linear relationship between blood uric acid and tear uric acid indicates that the developed method is a rapid, effective, and non-invasive technique for the determination of uric acid in tears.

Acridine-based dyes as high-performance near-infrared Raman reporter molecules for cell imaging.

A surface-enhanced Raman scattering (SERS) nanoprobe has been proven to be a promising tool for near-infrared (NIR) biomedical imaging and diagnosis because of its high sensitivity and selectivity. However, the development of NIR SERS reporters has been a bottleneck impeding the preparation of ultrasensitive SERS probes. Herein, we report the design and synthesis of a series of SERS reporters in the NIR region based on 10-methylacridine (AD). The AD nanotags (gold nanostar-AD molecules-BSA, AuNS-AD-BSA) exhibit appreciable SERS signals and can be detected at as low as the sub-picomole level. The results of in vitro imaging experiments show that it can be used in live-cell delineation.

Liquid Crystalline Elastomers Based on Click Chemistry.

Liquid crystalline elastomers (LCEs) have emerged as an important class of functional materials that are suitable for a wide range of applications, such as sensors, actuators, and soft robotics. The unique properties of LCEs originate from the combination between liquid crystal and elastomeric network. The control of macroscopic liquid crystalline orientation and network structure is crucial to realizing the useful functionalities of LCEs. A variety of chemistries have been developed to fabricate LCEs, including hydrosilylation, free radical polymerization of acrylate, and polyaddition of epoxy and carboxylic acid. Over the past few years, the use of click chemistry has become a more robust and energy-efficient way to construct LCEs with desired structures. This article provides an overview of emerging LCEs based on click chemistries, including aza-Michael addition between amine and acrylate, radical-mediated thiol-ene and thiol-yne reactions, base-catalyzed thiol-acrylate and thiol-epoxy reactions, copper-catalyzed azide-alkyne cycloaddition, and Diels-Alder cycloaddition. The similarities and differences of these reactions are discussed, with particular attention focused on the strengths and limitations of each reaction for the preparation of LCEs with controlled structures and orientations. The compatibility of these reactions with the traditional and emerging processing techniques, such as surface alignment and additive manufacturing, are surveyed. Finally, the challenges and opportunities of using click chemistry for the design of LCEs with advanced functionalities and applications are discussed.

Research Progress on Blue-Phase Liquid Crystals for Pattern Replication Applications.

Blue-Phase Liquid Crystals (BPLCs) are considered to be excellent 3D photonic crystals and have attracted a great deal of attention due to their great potential for advanced applications in a wide range of fields including self-assembling tunable photonic crystals and fast-response displays. BPLCs exhibit promise in patterned applications due to their sub-millisecond response time, three-dimensional cubic structure, macroscopic optical isotropy and high contrast ratio. The diversity of patterned applications developed based on BPLCs has attracted much attention. This paper focuses on the latest advances in blue-phase (BP) materials, including applications in patterned microscopy, electric field driving, handwriting driving, optical writing and inkjet printing. The paper concludes with future challenges and opportunities for BP materials, providing important insights into the subsequent development of BP.

Structural, Thermal, and Mechanical Characterization of a Thermally Conductive Polymer Composite for Heat Exchanger Applications.

Polymer composites are being considered for numerous thermal applications because of their inherent benefits, such as light weight, corrosion resistance, and reduced cost. In this work, the microstructural, thermal, and mechanical properties of a 3D printed polymer composite with high thermal conductivity are examined using multiple characterization techniques. Infrared spectroscopy and X-ray diffraction reveal that the composite contains a polyphenylene sulfide matrix with graphitic fillers, which is responsible for the high thermal conductivity. Furthermore, differential scanning calorimetry determines that the glass transition and melting point of the composite are 87.6 °C and 285.6 °C, respectively. Thermogravimetric analysis reveals that the composite is thermally stable up to ~400 °C. Creep tests are performed at different isotherms to evaluate the long-term performance of the composite. The creep result indicates that the composite can maintain mechanical integrity when used below its glass transition temperature. Nanoindentation tests reveal that modulus and hardness of the composite is not significantly influenced by heating or creep conditions. These findings indicate that the composite is potentially suitable for heat exchanger applications.

ZnO nanoparticle-based seed priming modulates early growth and enhances physio-biochemical and metabolic profiles of fragrant rice against cadmium toxicity.

BACKGROUND: Cadmium (Cd) is amongst the most toxic heavy metals that severely affects crop growth, whereas application of nanoparticles (NPs) to negate the toxic effects of heavy metals could be an effective management approach. In the present study, the seeds of two fragrant rice varieties i.e., Yuxiangyouzhan and Xiangyaxiangzhan under normal and Cd stress conditions i.e., 0 and 100 mg L- 1 applied with four levels of ZnO NPs i.e., 0, 25, 50, and 100 mg L- 1. RESULTS: Seed priming with ZnO NPs had no significant effect on the seed germination (p > 0.05) however, it substantially improved the seedling growth and other related physiological attributes under the Cd stress. The mean fresh weight of the shoot, and whole seedling was increased by 16.92-27.88% and by 16.92-27.88% after ZnO NPs application. The root fresh weight, root-shoot length was also substantially improved under ZnO NPs treatment. Moreover, application of ZnO NPs induced modulations in physiological and biochemical attributes e.g., the superoxide dismutase (SOD) activity in root and shoot, the peroxidase (POD) activity and metallothionein contents in root were increased under low levels of ZnO NPs. The α-amylase and total amylase activity were improved by ZnO NPs application under Cd Stress. Besides, modulation in Zn concentration and ZnO NPs uptake in the seedling were detected. The metabolomic analysis indicated that various pathways such as alanine, aspartate and glutamate metabolism, phenylpropanoid biosynthesis, and taurine and hypotaurine metabolism were possibly important for rice response to ZnO NPs and Cd. CONCLUSION: Overall, application of ZnO NPs substantially improved the early growth and related physio-biochemical attributes in rice. Our findings provide new insights regarding the effects of ZnO NPs on seed germination, and early growth of rice, and its potential applications in developing crop resilience against Cd contaminated soils.

Differential response of fragrant rice cultivars to salinity and hydrogen rich water in relation to growth and antioxidative defense mechanisms.

Salinity negatively effects the growth and productivity of crop plants; however, the effects of hydrogen rich water (HRW) on the early growth of fragrant rice under salinity stress are rarely investigated. In present study, two HRW treatments: foliar application (F-HRW) and irrigation (I-HRW) were applied on the two fragrant rice cultivars, Yuxiangyouzhan and Xiangyaxiangzhan, grown under normal and salt stress conditions, i.e., 0 and 150 mmol NaCl L-1, respectively. Plants without HRW application were grown as control (CK). Results showed that the dry weight per unit plant height (mg cm-1) was increased by 12.6% and 23.0% in F-HRW and I-HRW, respectively under salt stress as compared with CK. Application of HRW, regardless of the application method, modulated the antioxidant activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) while reduced malondialdehyde (MDA) contents under salt stress. Moreover, significant and positive relations were observed among total dry weight and shoot dry weight, dry weight per unit plant height, SOD and CAT activity in root. Overall, F-HRW application modulated the early growth and related physiological attributes in fragrant rice under salt stress whereas I-HRW was found to mitigate salt stress. Novelty statement: Involvement of endogenous H2 in plants for regulating various physiological functions is of great importance to stimulate and/or activate the antioxidant defense responses against oxidative stress; however, there is a lack of research in this aspect. The present study investigated the effects of hydrogen rich water (HRW) on the growth and physiological attributes of two fragrant rice cultivars grown under salt-stress. It was noteworthy to find that application of HRW either foliar application or irrigation improved the morphological characters, i.e., dry weight per unit plant height and enhanced the activities of antioxidants, i.e., peroxidase, superoxide dismutase and catalase whilst decreased the malonaldehyde content. Overall, the application of HRW modulates plant growth and physiological attributes in fragrant rice cultivars under salt-stress conditions. This study will be helpful in improving the early growth and/or stand establishment of fragrant rice nursery under saline conditions.